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TAF participated in the progression of various cancers, including PA via the release of soluble factors. Exosomes belonged to extracellular vesicles, which were revealed as a crucial participator in intercellular communication. However, the expression pattern and effect of TAF-derived exosomes remained largely unknown in PA. In the present study, we performed in silico analysis based on public RNA-seq datasets to generate the circRNA/miRNA regulatory network. The qRT-PCR, Western blotting, RNA pull-down, and luciferase assay were performed to investigate the effect of TAF-derived exosomes. TAF-derived exosomal circDennd1b was significantly upregulated in PA and promoted the proliferation, migration, and invasion of PA cells via sponging miR-145-5p in PA cells. In addition, miR-145-5p directly regulated One Cut homeobox 2 (ONECUT2/OC2) expression and inhibited the promoting effect of ONECUT2 on PA. We further demonstrated that ONECUT2 transcriptionally increased fibroblast growth factor receptor 3 (FGFR3) expression, which further activates the mitogen-activated protein kinases (MAPK) pathway, thus promoting PA progression. Moreover, the suppression of TAFs by ABT-263 and ONECUT2 by CSRM617 inhibited the growth of PA. In conclusion, our study illustrated that TAF-derived exosomal circDennd1b affected PA progression via regulating ONECUT2 expression, which provides a potential therapeutic strategy against aggressive PA.

Glycosylation is the most common posttranslational modification of proteins. Glycosyltransferase gene differential expression dictates the glycosylation model and is epigenetically regulating glioma progression and immunity. This study is aimed at identifying the glycosyltransferase gene signature to predict the prognosis and immune characteristics of glioma. The glycosyltransferase gene signature of glioma was identified in the TCGA database and validated in the CGGA database. Glioma patients were then divided into high- and low-risk groups based on risk scores to compare survival differences and predictive capacity. Subsequently, validation of glycosyltransferase gene signature merits by comparing with other signatures and utility in clinical judgment. The immune cell infiltration, immune pathways, and immune checkpoint expression level were also analyzed and compared in the high- and low-risk groups. Finally, the signature and its gene function were tested in our cohort and in vitro experiments. Eight glycosyltransferase genes were identified to establish the glycosyltransferase signature to predict the prognosis of glioma patients. The survival time was shorter in the high-risk group compared to the low-risk group based on glycosyltransferase signature and was confirmed in an independent external cohort. The glycosyltransferase signature displayed outstanding predictive capacity than other signatures in the TCGA and CGGA database cohorts. Furthermore, patients in the high-risk group were positively correlated with TAM infiltration, immune checkpoint expression level, and protumor immune pathways in TCGA cohorts. Validation of clinical tissue specimens revealed that the high-risk group was closely associated with infiltration of M2 TAMs. High-risk genes in the signature promote glioma proliferation, invasion, and macrophage recruitment in an in vitro validation of U87 and U251 cell lines. This carefully constructed that glycosyltransferase signature can predict the prognosis and immune profile of gliomas and help us evaluate subsequent macrophage-targeted therapies as well as other immune microenvironment modulation therapeutic strategies.

Background: Pituitary adenoma (PA) bone invasion results in adverse outcomes, such as reduced rates of complete surgical resection and biochemical remission as well as increased recurrence rates, though few studies have been conducted. Methods: We collected clinical specimens of PAs for staining and statistical analysis. Evaluation of the ability of PA cells to induce monocyte–osteoclast differentiation by coculturing PA cells with RAW264.7 in vitro. An in vivo model of bone invasion was used to simulate the process of bone erosion and evaluate the effect of different interventions in alleviating bone invasion. Results: We found an overactivation of osteoclasts in bone-invasive PAs and concomitant aggregation of inflammatory factors. Furthermore, activation of PKCθ in PAs was established as a central signaling promoting PA bone invasion through the PKCθ/NF-κB/IL-1β pathway. By inhibiting PKCθ and blocking IL1β, we were able to significantly reverse bone invasion in an in vivo study. Meanwhile, we also found that celastrol, as a natural product, can obviously reduce the secretion of IL-1β as well as alleviate the progression of bone invasion. Conclusions: By activating the PKCθ/NF-κB/IL-1β pathway, pituitary tumors are able to induce monocyte–osteoclast differentiation in a paracrine manner and promote bone invasion, which can be alleviated by celastrol.

Objective To analyse the application of a new narrow-band imaging (NBI) classification in the diagnosis of vocal cord leukoplakia by laryngologists with different levels of laryngoscopic experience and to explore the impact of NBI training programmes on laryngologists' identification of benign and malignant leukoplakia. Design Prospective multicentre study. Setting Tertiary hospitals. Participants Sixteen laryngologists were divided into less-experienced and experienced groups and received NBI training course. Thirty cases of vocal cord leukoplakia were investigated. Main outcome measures Diagnostic accuracy and interobserver agreement under white light imaging (WLI), before and after NBI training, were analysed among doctors with varying levels of experience. Results The accuracy in the less-experienced group was significantly lower than that of experience group (0.59 vs 0.69) under WLI. There was no significant difference in the diagnostic accuracy between the less-experienced group and the experienced group before NBI training (0.75 vs 0.74) and after NBI training (0.79 vs 0.83). NBI training could improve the interobserver agreement from fair or moderate to good agreement. Conclusion The new NBI diagnostic classification is helpful for identifying benign and malignant vocal cord leukoplakia. In addition, the NBI training programme can improve the diagnostic accuracy and interobserver agreement of less-experienced doctors to the level of experienced laryngologists.

Based on the structure-oriented lumping method, a molecular-level reaction kinetic model of the delayed coking process, which adopted 24 structural increments to construct the feed molecular matrix containing 2,944 molecules, was established with a reaction network containing 74,581 reactions using MATLAB. The reliability of the model was verified by experimental results. According to the discriminant rules of structural increments, 173 structural vectors in gasoline and 1,132 structural vectors in diesel were classified into different group compositions, respectively. The model could track the reaction path of any specific molecule in the complex thermal cracking reaction network. The influences of operation conditions such as recycle ratio on the product distribution could be discovered through the calculation of the molecular-level model, which is helpful for the process optimization and precise regulation of product composition for the delayed coking plants.

Objective: To explore the effects of the TP (Taxol plus Platinol) regimen and the PF (Platinol plus fluorouracil) regimen on patients with advanced laryngeal cancer and on the patients’ VEGF-C (vascular endothelial growth factor C) and survivin genes. Methods: 42 patients with locally advanced laryngeal cancer treated in our hospital from June 2018 to October 2020 were recruited as the study cohort. The patients were assigned into a control group (21 cases) or an observation group (21 cases). The control group was administered the PF regimen, and the observation group was administered the TP regimen. Both groups were treated for four consecutive courses. The clinical efficacy of the two groups of patients was observed, and the two groups’ treatment effects, their serum VEGF-C, and survivin levels, and their adverse reactions were compared. Results: A superior clinical efficacy was observed in the observation group (85.7%) than in the control group (57.1%) (P0.05). After the treatment, apparently lower serum VEGF-C and survivin levels in the observation group were measured, and both groups witnessed a decline in their levels (P0.05). Conclusion: The TP regimen in the treatment of laryngeal cancer can reduce the VEGF-C and survivin levels in patients and has a better therapeutic effect, so it is worthy of clinical promotion.

Biao Xing,1,* Xiao-Feng Qiao,2,* Yan-Hua Qiu,3 Xin Li4,5 1Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, People’s Republic of China; 2Department of Otorhinolaryngology, Shanxi Provincial People’s Hospital Affiliated to Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Otolaryngology, The First People’s Hospital of Linhai City, Linhai, Zhejiang, People’s Republic of China; 4Department of Otorhinolaryngology, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing, People’s Republic of China; 5School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin LiDepartment of Otorhinolaryngology, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing, People’s Republic of ChinaEmail lixinlx8@tom.comBackground: Previous evidence demonstrates that the long non-coding RNA (lncRNA) TMPO antisense RNA 1 (TMPO-AS1) is involved in the aggressiveness of several cancers. Nevertheless, its functions in nasopharyngeal carcinoma (NPC) are unclear.Methods: qRT-PCR was used to evaluate the levels of TMPO-AS1 and miR-320a in NPC tissues. Furthermore, the growth and invasiveness of NPC cells were evaluated by colony formation and Transwell assays. The protein expression ofSRY-Box Transcription Factor 4 (SOX4) was observed by Western blotting and immunohistochemistry. Bioinformatic prediction and luciferase reporter assays were used to explore the interaction between miR-320a and TMPO-AS1. The transplanted model was employed to disclose the interference of TMPO-AS1 in the tumor growth of NPC cells in vivo.Results: We found that TMPO-AS1 was distinctly upregulated in NPC. Downregulation of TMPO-AS1 restrained aggressiveness-associated traits in NPC cells. Nevertheless, upregulation of TMPO-AS1 yielded the opposite results. Further studies revealed that lncRNA TMPO-AS1 acts as a “sponge” for miR-320a, resulting in increased levels of SOX4 in NPC cells. Finally, TMPO-AS1 silencing suppressed tumor growth of NPC cells in vivo.Conclusion: Collectively, these results reveal the presence of a novel TMPO-AS1/miR-320a/SOX4 pathway associated with NPC progression, suggesting that lncRNA TMPO-AS1 may be a potential therapeutic target for NPC.Keywords: TMPO-AS1, nasopharyngeal carcinoma, invasion, SOX4

Background Hepatitis B virus infection remains an important global public health problem. Approved alum-adjuvanted vaccines are well tolerated but require three doses and have reduced immunogenicity in adults. A two-dose vaccine containing hepatitis B surface antigen combined with a novel, Toll-like receptor 9 agonist adjuvant (HBsAg-1018 [HEPLISAV–B®]) has demonstrated significantly higher seroprotection rates than a three dose vaccine. Methods A post hoc analysis compared the safety of HBsAg-1018 with HBsAg-Eng (Engerix-B®), in three randomized, observer-blinded, active-controlled, multi-center phase 3 trials in adults. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. Results Post-injection reactions, adverse events, medically attended adverse events, and new-onset immune-mediated adverse events were balanced between vaccine groups. Anti-nuclear antibodies, anti-double stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and antiphospholipid antibodies were balanced between groups. A transient increase in anti-beta2 glycoprotein 1 IgM was observed in the HBsAg-1018 group but was not associated with a thrombotic event. Serious adverse events and deaths were generally balanced between groups. Conclusion HBsAg-1018 had a similar safety profile to HBsAg-Eng. With improved immunogenicity and fewer doses over a shorter time, HBsAg-1018 has the potential to provide improved seroprotection and a significant public health benefit to adults 18 years of age or older.

The influencing factors of the equipment support activity process have the characteristics of nonlinearity, high dimension, many constraints, random uncertainty and fuzzy uncertainty. Monte Carlo method can solve the above problems commendably. This paper analyzes the main equipment support activity process and establishes the sampling plan and simulation model of the medium maintenance process based on Monte Carlo method, and the simulation result verifies a fact that the medium maintenance time can be effectively reduced when parallel operation on some procedures is used. It has a practical value and can give good advice to achieve the capability of equipment supportability.

Time for single vehicle combat preparation (TSVCP) is an important characteristic parameter for the operational support feature of armored vehicle. During the development phase, how to validate the TSVCP of armored vehicle through analytic method is a difficult issue in analysis and validation of vehicle supportability. This paper uses Monte Carlo approach and builds a working model for single vehicle combat preparation (SVCP) of armored vehicle, thus realizes the prediction and analysis of the TSVCP of armored vehicle, and finally validates the effectiveness of the approach by example.

In order to describe the reaction network and investigate the conversion behavior of sulfur compounds in delayed coking process, a molecular-level reaction kinetic model was established with a reaction network consisting of 81,081 reactions based on the structure-oriented lumping method. A feed molecular matrix containing 2,944 structural vectors was constructed with 24 structural increments based on the characteristics of the vacuum residue molecular composition. The reliability of the model was verified by industrial data. Through the calculation of the SOL model, the sulfur compounds in gasoline were expressed as 57 structural vectors, which were divided into thiophenes, mercaptans and thioethers according to the discriminant rules. The conversion law of sulfur compounds was investigated by tracking the reaction path of molecules in the reaction network. The SOL model could calculate the distribution of sulfur compounds in coking gasoline. The contents of thiophene molecules increased with the carbon numbers. Ethyl mercaptan and propyl mercaptan had higher content in mercaptans. The SOL model can reveal the influences of reaction conditions on sulfur compounds conversion in delayed coking process at the molecular level, which contributes to the accurate control of sulfur content in coking gasoline.

A molecular level model for Fluid Catalytic Cracking (FCC) process was established based on the Structure-Oriented-Lumping (SOL) method to investigate the effects of the diameter expanding reactor on the product distribution. According to the molecular composition characteristics of feed oil, 24 structural increments were adopted to construct a molecular matrix containing 4539 molecules. Combined with the SOL reaction rules, a reaction network consisting of 118,272 reactions was established using MATLAB. The contents of 266 molecules in gasoline and 1189 molecules in diesel oil were calculated using the molecular level models of diameter expanding reactor and conventional reactor. The olefins content in gasoline, which is the summarization of 83 olefins molecules, increased as the reaction temperature went up. Compared with the conventional reactor, the ratio of isopentane to pentene in the diameter expanding reactor increased from 1.38 to 2.59 and the ratio of toluene to methylcyclohexane increased from 2.69 to 3.94. The model illustrated that the diameter expanding reactor could enhance the hydrogen transfer and isomerization reactions from the molecular level to reduce the olefins content and improve the iso-paraffins content in gasoline. The model could describe the molecular level product distribution from the reactor inlet to the outlet.

The oxidizability of NO3 radical in the nocturnal atmosphere is comparable with that of diurnal OH radical. Given the importance of NO3 radical in the nocturnal chemical process, accurate measurement of its concentration and analysis its nocturnal chemical process have important significance. The article introduces cavity ring-down spectroscopy (CRDS) instrument which is applied to measure atmospheric NO3 radical. Light from a red laser diode (the wavelength is 662 nm and line width is 0.3 nm) is coupled on-axis into an optical cavity formed by a pair of high-reflectivity mirrors (R≥99.998 5%) to achieve an effective absorption path length of approximately 20km. And it researches nocturnal chemical process of NO3 radical in view of the fall and winter heavy traffic areas. The measurement of NO3 radical with cavity ring-down spectroscopy was performed in Beijing from October 29 to November 15, 2014. During the observation, the concentration of NO3 radical is relatively low with the maximum of NO3 radical concentration of 50pptv and the average of its concentration of approximately10 pptv. Combining of NO2, O3 and NO data, the observation results are analyzed. The NO3 production rates ranging from 0.04 to 1.03 pptv·s-1 were calculated throughout the observation, and NO3 lifetime averaged at 68 s. The NO3 loss process in the atmosphere is further analyzed. Combining of related auxiliary data, the influence of different humidity as well as particulate matter concentrates on the atmospheric NO3 removal is researched. When atmospheric RH≥60% and PM2.5 concentration mainly greater than 60 μg·m-3，the correlation coefficient of the logarithmic correlation between NO3 lifetime and NO2 mixing ratio is 0.79，NO3 is mainly removed by the indirect loss process; however, when atmospheric RH≤40% and the concentration of PM2.5 mainly smaller than 60 μg·m-3, because of the observation site is close to national highway and influenced by local pollution source, the direct loss process is main; When atmospheric 40%RH60%, the results show the direct loss process and the indirect loss process both exist and cannot be ignored.

A method for dye laser wavelength correction applied for the measurement of OH radical with FAGE (Fluorescence Assay by Gas Expansion) is researched in this article. Sufficiently stable concentration of OH radical is produced with thermal dissociation of H2O by using an alumel filament and the fluorescence is excited with 282 nm laser in a low pressure cell. The fluorescence is detected with a photomultiplier and a high speed data acquisition card, while the laser light is monitored by a photodiode, and both signals are handled by a LabVIEW program for further analysis. The data acquisition card is triggered by a positive TTL pulse generated by a digital delay generator, which is triggered by a rising edge of a synchronized output pulse of the dye laser. The LabVIEW program is used to determine the location of the OH excited line according to the fluorescence intensity of OH radical when the frequency of the dye laser is scanned. By scanning dye laser wavelength range in 281.97~282.28 nm, excitation spectrum of OH radical is recorded. In order to optimize system parameters and achieve a high signal-to-noise ratio, the effects of the humidity, oxygen concentration, mass flow and pumping speed on fluorescence intensity and lifetime are studied at Q12 line and less than ±1.9% fluctuations of the fluorescence intensity is obtained. With analysis of the reaction mechanism of the thermal dissociation of H2O, it is concluded that reaction of oxygen and water is a major source of OH radical. Laser output wavelength is scanned in a small range around Q12 line to find out the exact exciting line and then correct the laser’s output, which might slightly shift due to the environmental change and leads to reduction of fluorescence intensity. The wavelength correction procedure is implemented many times and the results show that the systematic error of the instrument is less than 0.1 pm. According to the experimental results, this method meets the needs of quantitative accurate measuring tropospheric OH radical by FAGE.

A cavity ring-down spectroscopy (CRDS) instrument for measuring atmospheric NO3 radical developed in our laboratory is presented in detail. Light from a red laser diode (661.85 nm) is coupled on-axis into an optical cavity formed by a pair of high-reflectivity mirrors (R≥99.9985%) to achieve an effective absorption path length of approximately 20 km. The detection limit of the NO3 radical determined by Allan variance for the field observation with high particles is approximately 3.2 pptv (2σ, 10 s). The transmission efficiency of the NO3 radical in the system is calibrated, including the filter loss and surface loss. Moreover, measurable interferences from NO2, O3 and water vapor are also discussed. Considering the influence of inlet transmission efficiency and other factors, the instrument accuracy for NO3 radical measurement is approximately ±8% (1σ). The measurement of NO3 radical was performed at a suburb site in Beijing under the situation of high particles concentration (PM2.5 approximately several tens to 150 µg/m3) from October 26 to November 11, 2014. The NO3 radical concentration during the period is relatively low with the maximum value of 38 pptv. The observation results on October 29, combining NO2, O3 and NO data, are briefly analyzed. The experimental results demonstrate that this compact CRDS instrument has the potential for NO3 radical measurements in the field with high particles.

To observe the efficacy and safety of bloodletting and cupping for cervical radiculopathy. The randomized controlled clinical trial was conducted in five centers. A total of 183 eligible subjects were randomly allocated into a bloodletting group (n=68), an acupuncture group (n=56) and a combined group (n=59). Patients in the bloodletting group were treated with bloodletting at Dazhui (GV 14) and Jianjing (GB 21) on the affected side, coupled with 5–10 min of cupping, 5 mL blood for each cup, 2–3 cups for one treatment. Patients in the acupuncture group were treated with needling cervical Jiaji (EX-B 2) points and Jianjing (GB 21) on the affected side. The needles were retained for 30 min. Patients in the combined group were treated with both methods. The treatment in all three groups were done once every three days, twice a week, 4 weeks for a course of treatment, for a total of 1–3 courses. Then the therapeutic efficacy was evaluated using scores of visual analogue scale (VAS), neck disability index (NDL) and clinical assessment scale (CAS) before treatment and after 1, 2 and 3 courses of treatment. The scores of VAS, NDI and CAS in all three groups were significantly decreased after 1, 2 and 3 courses of treatment (all P 0.05). Bloodletting and cupping share the similar effect with acupuncture in pain relief and improvement of quality of life in patients with cervical radiculopathy.

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.

采用化学自组织方法在SrTiO 3 (100)及Nb-掺杂 SrTiO 3 (100) 单晶衬底上制备了外延BiFeO 3 纳米岛, 并利用X射线衍射、扫描电子显微镜和原子力显微镜对纳米岛的相结构及形貌进行了表征. 结果表明, 在650~800℃下后退火1h可获得外延的BiFeO 3 纳米岛, 岛横向尺寸在50~150 nm之间, 纵向尺寸在6~12 nm之间. 随着纳米岛后退火温度的升高, 其(100)面内的几何形貌由三角形状转向四边形状, 然后再趋向于长棒状. 利用压电力显微镜, 对单个BiFeO 3 纳米岛(横向尺寸~50 nm, 高度12 nm)的铁电特性进行表征. 结果表明, 单个外延BiFeO 3 纳米岛内存在分形铁电畴和自偏压极化现象, 其中自偏压极化现象来源于外延BiFeO 3 纳米岛与SrTiO 3 单晶衬底之间的界面应力.

Background and Objectives: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembrolizumab is a PD-1 inhibitor that has demonstrated activity in HNSCC with ORR of 14%. Study DV3-MEL-01 (NCT02521870) assesses the safety and preliminary efficacy of SD-101 in combination with pembrolizumab in patients with recurrent or metastatic HNSCC. Methods: In phase 2 expansion cohort for anti-PD-1 treatment naïve HNSCC patients, SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses) at 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks. Responses are assessed per investigator using RECIST v1.1/irRECIST. Preliminary Data and Results: 16 anti-PD-1 treatment naïve HNSCC patients are enrolled to date: median age 65 y/o, male 94%, ECOG PS1 63%, median prior lines of therapy 1. SD-101 safety profile consists of flu-like symptoms and injection-site reactions. Grade≥3 treatment-related AEs observed to date included influenza-like symptoms, myalgia, headache, injection site pain and swelling, and fatigue with each of the toxicities occurring in 1 patient (6.7%). No increase in frequency of known pembrolizumab immune-related AEs has been observed to date. ORR in evaluable pts (n=10) was 40% (4 PRs; 1 SD, 5 PDs with 1 still on treatment). The duration of response will be characterized when follow-up data become more mature. Conclusions: In anti-PD-1 treatment naïve HNSCC patients, SD-101 in combination with pembrolizumab showed a promising response rate and has been well tolerated. Full accrual of subjects in this cohort is ongoing. Citation Format: Ezra Cohen, Sarwan Bishnoi, Douglas E. Laux, Deborah Wong, Asim Amin, Lisle Nabell, Emmett V. Schmidt, Biao Xing, Abraham C. Leung, Robert Janssen. Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT098.

Stability data are often collected to determine the shelf life of certain characteristics of a pharmaceutical product, for example, a drug's potency over time. Statistical approaches such as the linear regression models are considered as appropriate to analyze the stability data. However, most of these regression models in both theory and practice rely heavily on their underlying parametric assumptions, such as normality of the continuous characteristics or their transformations. In this article, we propose and study some rank-based regression procedures for the stability data when the linear regression models are semiparametric with unspecified error structure. Numerical studies including Monte Carlo simulations and practical example are demonstrated with the proposed procedures as well.

9550 Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH > 1 ULN 27%, ≥ 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (≥20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented. Clinical trial information: NCT02521870.

Introduction: Prior studies have shown preliminary clinical efficacy in combining CpG-ODN with radiation therapy (XRT) to patients with indolent B-cell lymphoma. We report interim Phase 1/2 data of combination XRT and SD-101, a synthetic class C CpG-ODN TLR9 agonist, selected for the strong induction of type I interferon. Methods: This dose-escalation Phase 1/2 trial enrolled patients with untreated indolent B-cell lymphoma having at least 2 measurable lesions (one palpable). The primary endpoints were safety and alpha-interferon-gene induction. Secondary endpoints included efficacy assessment using Cheson (1999) criteria and quantification of changes in tumor-infiltrating lymphocytes. A single lesion was treated with XRT (2 Gy daily X 2 days) followed by a single intratumoral dose of SD-101 (same lesion). 4 additional doses of intratumoral SD-101 were given weekly over next 4 weeks. The treated lesion and distal lesions were monitored during the study. Pharmacodynamic assessment included flow cytometry analysis of immune infiltrates in an FNA sample of the treated tumor and RT-PCR RNA assay of whole blood to assess induction of alpha-interferon genes. Efficacy assessment included imaging (CT at 3, 6, and every 6 months thereafter). Results: As of 01 Aug 2016, 13 patients were treated with escalating doses of SD-101 at 1, 2, 4 or 8 mg/dose. There were no dose limiting toxicities. The majority of related adverse events (AEs) were Grade 1 (mild). The most common were flu-like symptoms (chills, headache, malaise, myalgia), typically resolving within ≤ 48 hours without requiring intervention (e.g., acetaminophen). An induction of alpha-interferon genes occurred at all dose levels with a similar level of induction. For the dose expansion phase, 15 patients were enrolled at 1 mg (6) and 8 mg dose group (9). Similar to dose escalation phase, the most common related events were again flu-like symptoms, typically resolving within ≤ 48 hours mitigated with acetaminophen. There was one dose delay for Grade 3 neutropenia in one patient (1 mg) that resolved following drug interruption. Twenty-nine Grade 3 transient flu-like symptoms were reported for four patients (44%) who received the 8 mg dose (e.g., chills headache, malaise, myalgia, and fatigue). Only one of the four patients experienced all 5 Grade 3 flu-like symptoms after intratumoral injection. There were no grade 4 or serious events reported, and no patient discontinued due to an adverse event. A reduction in tumor sizes was observed in the study over time (see Figure 1). At Day 90 the median changes in the product of diameters from baseline were -46.1% and -10.2% for treated tumor and distal tumors, respectively. At Day 540, the median changes were -68.6% and -24.1%, respectively. In patients with follicular lymphoma (largest subgroup), preliminary data suggest a higher percentage of CD8+ T cells in the treated lesion (FNA at day 8) correlated with an increased abscopal response. Conclusions: Intratumoral SD-101 following radiation therapy has been well tolerated and preliminary efficacy, promising. Abscopal anti-tumor activity was observed with preliminary data suggesting that a higher percentage of CD8+ T cells in the treated lesion correlated with an increased abscopal response seen in follicular lymphoma. Enrollment is ongoing with an option for cycle 2 retreatment. Disclosures Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Bartlett:Gilead: Consultancy. Leung:Dynavax: Employment. Peterkin:Dynavax: Consultancy. Xing:Dynavax: Employment. Coffman:Dynavax: Employment. Janssen:Dynavax: Employment. Candia:Dynavax: Employment.

Although sEH inhibitors are well studied in inflammatory and cardiovascular diseases, their effects on gliomas are unclear. In this study, we investigated the effects of t-AUCB, a more potent and selective sEH inhibitor, on U251 and U87 human glioblastoma cell lines and the HepG2 human hepatocellular carcinoma cell line. Our results showed that t-AUCB efficiently inhibited sEH activities in all three cell lines (the inhibition rate was more than 80% in each) and suppressed U251 and U87 cell growth in a dose-dependent manner, but exhibited no cell growth inhibition on HepG2. We detected high levels of phosphorylated NF-κB-p65 (Ser536) in t-AUCB-treated U251 and U87 cells, and then found that the NF-κB inhibitor PDTC can completely abolish t-AUCB-induced growth inhibition. This indicated that t-AUCB suppresses U251 and U87 cell growth by activating NF-κB-p65. Moreover, we found that t-AUCB induces cell-cycle G0/G1 phase arrest by regulating Cyclin D1 mRNA and protein levels and CDC2 (Thr161) phosphorylation level. We propose to further test this promising reagent for its anti-glioma activity in clinical relevant orthotopic brain glioma models.

e76 have had prior transplant (69.9% v 20.6%) v pts 70 yr. Median PFS for pts

Identification of transcription factor binding sites (regulatory motifs) is a major interest in contemporary biology. We propose a new likelihood based method, COMODE, for identifying structural motifs in DNA sequences. Commonly used methods (e.g. MEME, Gibbs motif sampler) model binding sites as families of sequences described by a position weight matrix (PWM) and identify PWMs that maximize the likelihood of observed sequence data under a simple multinomial mixture model. This model assumes that the positions of the PWM correspond to independent multinomial distributions with four cell probabilities. We address supervising the search for DNA binding sites using the information derived from structural characteristics of protein-DNA interactions. We extend the simple multinomial mixture model to a constrained multinomial mixture model by incorporating constraints on the information content profiles or on specific parameters of the motif PWMs. The parameters of this extended model are estimated by maximum likelihood using a nonlinear constraint optimization method. Likelihood-based cross-validation is used to select model parameters such as motif width and constraint type. The performance of COMODE is compared with existing motif detection methods on simulated data that incorporate real motif examples from Saccharomyces cerevisiae. The proposed method is especially effective when the motif of interest appears as a weak signal in the data. Some of the transcription factor binding data of Lee et al. (2002) were also analyzed using COMODE and biologically verified sites were identified.

Blinded estimation of variance allows for changing the sample size without compromising the integrity of the trial. Some of the methods that estimate the variance in a blinded manner either make untenable assumptions or are only applicable to two-treatment trials. We propose a new method for continuous endpoints that makes minimal assumptions. The method uses the enrollment order of subjects and the randomization block size to estimate the variance. It can be applied to normal or non-normal data, trials with two or more treatments, equal or unequal allocation schemes, fixed or random randomization block sizes, and single or multi-centre trials. The variance estimator is unbiased and performs best when the randomization block size is the smallest. Simulation results suggest that for many commonly used randomization block sizes the proposed estimator is expected to perform well. The proposed method is used to estimate the variance of the endpoint for two trials and is shown to perform well by comparison with its unblinded counterpart.

Transcriptional regulation is one of the most important means of gene regulation. Uncovering transcriptional regulatory networks helps us to understand the complex cellular process. In this paper, we describe a statistical approach for constructing transcriptional regulatory networks using data of gene expression, promoter sequence, and transcription factor binding sites. Our simulation studies show that the overall and false positive error rates in the estimated transcriptional regulatory networks are expected to be small if the systematic noise in the constructed feature matrix is small. Our analysis based on 658 microarray experiments on yeast gene expression programs and 46 transcription factors suggests that the method is capable of identifying significant transcriptional regulatory interactions and uncovering the corresponding regulatory network structures.

Transcriptional regulation is one of the most important means of gene regulation. Uncovering transcriptional regulatory network helps us to understand the complex cellular process. In this paper, we describe a comprehensive statistical approach for constructing the transcriptional regulatory network using data of gene expression, promoter sequence, and transcription factor binding sites. Our simulation studies show that the overall and false positive error rates in the estimated transcriptional regulatory network are expected to be small if the systematic noise in the constructed feature matrix is small. Our analysis based on 658 microarray experiments on yeast gene expression programs and 46 transcription factors suggests that the method is capable of identifying important transcriptional regulatory interactions and uncovering the corresponding regulatory network structures.

We describe a calculation ofT c (P, H) in a model of a disordered superconductor which is based on the de Gennes-Skal-Shklovskii (dGSS) picture of the large cluster in a percolation system. The calculation is done by carrying out successive decimations on the Landau-Ginzburg Hamiltonian describing the ‘links’ in the model. We calculateT c (P, H) in the presence of longitudinal magnetic field by evaluating the renormalized Landau-Ginzburg coupling when the renormalized Landau-Ginzburg length equals the percolation link length in the dGSS picture and obtain the approximate analytic form ofT c (P, H).

Background: Lenalidomide with dexamethasone (Rd) is a standard of care used for pts with relapsed multiple myeloma (RMM). The randomized, open-label, multicenter, phase 3 study ASPIRE (NCT01080391) is comparing carfilzomib, lenalidomide, and dexamethasone (KRd) to Rd in pts with RMM. The primary end point is progression-free survival (PFS; assessed by an independent review committee). Secondary end points include overall survival (OS), overall response rate (ORR), duration of response (DOR), health-related quality of life (EORTC QLQ-C30 Global Health Status/QoL), and safety. Methods: Adults with RMM who received 1–3 prior regimens were eligible. Pts were randomized (1:1) to receive KRd or Rd and were stratified by β2-microglobulin levels ( Results: Data are presented for KRd followed by Rd throughout the abstract. Between July 2010 and March 2012, 792 pts from 20 countries were randomized. Baseline characteristics were balanced between the 2 groups. Median age was 64.0 years (range: 31.0‒91.0). Pts received a median of 2 prior regimens in each group. In both the KRd and Rd groups, 66% of pts received prior bortezomib; 20% of pts in each arm received prior R. Median treatment exposure was 22 cycles (KRd) and 14 cycles (Rd). At the time of the prespecified interim analysis, the study met the primary end point for PFS (HR=0.69; 95% confidence interval [CI]: 0.57–0.83; P Conclusion: The addition of carfilzomib to lenalidomide and dexamethasone in pts with RMM resulted in a statistically significant and clinically meaningful improvement in PFS. KRd had an acceptable safety and tolerability profile and represents a potential new standard of care. Disclosures Stewart: Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding; Celgene: Consultancy. Off Label Use: Carfilzomib is approved in the United States for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. ASPIRE is a randomized, multi-center, phase 3 study investigating the use of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1–3 prior regimens.. Dimopoulos:Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spicka:Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Hájek:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Siegel:Onyx: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Niesvizky:Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Jakubowiak:Onyx Pharmaceticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Millinnium: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Research Funding, Speakers Bureau; Takeda Celgene: Research Funding, Speakers Bureau; Bristol-Myers: Research Funding, Speakers Bureau. Zojwalla:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Tonda:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Xing:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria; Janseen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Inc,: Consultancy, Honoraria; Array BioPharma: Honoraria.